Clinical impact of the hepatitis C virus mutations in the era of directly acting antivirals

Abstract

Introduced in 2013-2014, the second- and third-wave directly acting antivirals (DAAs) have strongly enhanced the efficacy and tolerability of anti-HCV treatment, with a sustained virological response (SVR) in 90-95% of cases treated. The majority of patients who did not achieve an SVR were found to be infected with HCV strains with a reduced susceptibility to these drugs. Indeed, the high error rate of the viral polymerase and a fast virion production (100-fold higher than the human immunodeficiency virus) result in a mixture of viral genetic populations (quasi-species) pre-existing treatment initiation. These mutants occur frequently in the NS5A region, with a moderate frequency in the NS3/4A region and rarely in the NS5B region. Treatment-induced resistant mutants to NS5A DAAs persist for years after treatment discontinuation, whereas those resistant to the NS3 DAAs have a shorter duration. This review focuses on the type and prevalence of viral strains with a reduced sensitivity to DAAs, their clinical impact and influence on the response to treatment and, consequently, on treatment choice for DAA-experienced patients. J. Med. Virol. 88:1659-1671, 2016. © 2016 Wiley Periodicals, Inc.

Virological patterns of HCV patients with failure to interferon‐free regimens

“…As regards the HCV regions, the prevalence of RASs in the NS3 region was medium (30.8‐57.9%) in all three groups of patients, while it was high (71.8%) in the NS5A region in the optimal regimen group, and low in NS5B, both for nucleoside and non‐nucleoside inhibitors (15.8‐25.6% and 0‐12.8%, respectively). This result is in line with the fact that the NS5B inhibitors are DAAs with a high barrier to resistance and the presence of RASs at sofosbuvir failure was reported to be infrequent . On the contrary, the high prevalence of NS5A RASs is linked to the low barrier to resistance of the current NS5A inhibitors.…”

Distribution of Hepatitis C Virus Genotypes and Subtypes in the Metropolitan Area of Naples, Italy, in the Era of Interferon-Free Regimens

“…Thus, the identification of the HCV genotype in a geographical area with a high prevalence of HCV, such as Naples, is an important issue since, in the DAA era, HCV genotypes and subtypes remain cornerstones for the management of chronic HCV infections. In fact, the type and duration of IFN-free regimens differ for the various genotypes and subtypes: protease inhibitors (simeprevir, paritaprevir, and grazoprevir) are indicated only for genotypes 1 and 4, while for genotypes 3 and 2 only an anti-NS5A plus anti-NS5B combination is indicated [12] . In addition, the duration of the IFN-free regimen is only 3 months for patients with genotype 1b, 2, or 4, while it is 6 months for those with genotype 1a or 3.…”

“…The error-prone nature of the HCV polymerase and the accumulation of mutations in a small hypervariable region in the envelope-encoding genes generate a high level of variability. This variability translates into the existence of 7 major HCV genotypes (with 30-35% variation at the nucleotide level), 67 subtypes (with less than 15% difference at the nucleotide level), each composed of a myriad of viral quasi-species, and 9 recombinant forms (e.g., the most frequently reported genotype 2k/1b, which has multiple isolates) [11,12] . The geographical distribution of HCV genotypes is significantly variable [13,14] .…”

State of the Art, Unresolved Issues, and Future Research Directions in the Fight against Hepatitis C Virus: Perspectives for Screening, Diagnostics of Resistances, and Immunization

“…Y93H is the most frequent baseline NS5A RAV in G1b, followed by L31M/V, while NS5A RAVs are less frequent in G1a [86, 87, 101–103]. L31M confers low-medium level resistance to daclatasvir and ledipasvir, while Y93H/N confers medium-high level resistance to all three approved NS5A inhibitors [100, 104] in G1a but only for ledipasvir in G1b.…”

“…The principal mutation that confers decreased susceptibility to sofosbuvir is S282T and more recently the variants L159F (with/without L320F and C316N) and V321A were detected in patients with failed treatment [108]. M414T and S556G variants were observed in G1a and S556G in G1b patients who did not achieve an SVR after a nonnucleoside analog inhibitor dasabuvir-based regimen [104]. The most relevant NS5B RAVs are reported in Table 5.…”